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Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

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Cancer Drug Resistance 2019年第3期2卷 428-446页

作者： Nilay Shah Division of pediatric Hematology/Oncology/bmt Nationwide Children’s HospitalColumbusOH 43205USA Department of pediatrics The Ohio State University College of MedicineColumbusOH 43210USA.

While advances in the treatment of pediatric cancers have improved survival to>80%across all tumor types,drug resistance continues to limit survival for a considerable number of *** review the known mechanisms of resistance in pediatric cancers,including processes that impair conventional chemotherapies,newer classes of targeted small molecule antineoplastic drugs,and monoclonal *** highlight similarities and differences in treatment approach and resistance between pediatric and adult *** also discuss newer areas of research into drug resistance,including extracellular and immune factors.

关键词： Tumor microenvironment drug efflux chemoresistance inhibition of apoptosis BCL2 pediatric cancer

A dry-electrode enabled ECG-on-Chip with arrhythmia-aware data transmission

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Science China(Information Sciences) 2025年

作者： Xinzi XU Yanxing SUO Yang ZHAO Peiyi ZHOU Xiao HAN Qiao CAI Min WANG Jiajun YUAN Liebin ZHAO Yongfu LI Guoxing WANG Yong LIAN Department of Micro-Nano Electronics and MoE Key Lab of Artificial Intelligence Shanghai Jiao Tong University pediatric AI Clinical Application and Research Center Shanghai Engineering Research Center of Intelligence Pediatrics (SERCIP) Child Health Advocacy Institute Shanghai Children's Medical Center School of MedicineShanghai Jiao Tong University Shanghai Engineering Research Center of Intelligence pediatrics (SERCIP) Xin Hua Hospital Affiliate to Shanghai Jiao Tong University School of Medicine

Early detection and treatment of cardiovascular diseases (CVDs) can be significantly enhanced through the use of flexible wearable electrocardiogram (ECG) sensors, potentially reducing CVD-related mortality. This paper introduces an ECG-on-Chip (EoC) solution tailored for flexible ECG sensors, incorporating novel features to address common challenges in wearable ECG technology. The EoC integrates a chopper-stabilized capacitively-coupled instrumentation amplifier (CS-CCIA),ensuring a high common-mode rejection ratio (CMRR) and low noise performance. Performance is further boosted via a positive feedback loop (PFL) and a programmable gain amplifier (PGA) with shared on-chip calibration logic, which enhances input impedance and minimizes gain variability to ensure consistent algorithm performance. Additionally, a secondary chopping technique is employed to further reduce noise, achieving an input-referred noise level of 454 nVrms. The embedded algorithm within the EoC is designed to extract clinically meaningful features, facilitating robust real-time arrhythmia analysis. Fabricated using a 0.18μm CMOS process, the EoC consumes 14.9μW with a supply voltage of 1.2 V. The algorithm’s efficacy has been validated over 0.4 million heartbeats, demonstrating a sensitivity of over 99.7%for R-peak detection and 98.3%for arrhythmia analysis. To demonstrate practical application, the EoC has been integrated with a commercial Bluetooth low energy (BLE)transceiver, forming a wireless arrhythmia monitoring sensor equipped with dry electrodes. This system consumes 292.04μW in arrhythmia-aware transmission mode, supporting 13 days of operation with a 30 mAh thin-film battery.

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Malonylcarnitine in Newborns with Non-syndromic Cleft Lip with or without Cleft Palate

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International Journal of Oral Science 2010年第3期2卷 136-141页

作者： Kamil Konrad Hozyasz Mariusz Oltarzewski Zofia Dudkiewicz pediatric Department Institute of Mother and Child Neonatal Screening Laboratory Institute of Mother and Child Department of pediatric Surgery Institute of Mother and Child

Aim Malonyl-CoA is regarded as a key signaling molecule in mammalian ceils. It is converted to acetyl-CoA, and to a lesser extent, to malonyl acid and malonylcamitine （C3DC）. Availability of carnitine has been reported to be essential for the developing fetus. The objectives of the present study were to analyze associations of malonylcarnitine, acetylcarnitine （C2）, and free carnitine （CO） in subjects with orofacial clefts. Methodology We performed a retrospective analysis of carnitine concentration obtained from a newborn screening program carried out in our institution. Concentrations of whole blood malonylcarnitine, acetylcarnitine, and free carnitine were measured using tandem mass spectrometry. The study group consisted of 51 children with nonsyndromic cleft lip with or without cleft palate. In total, 106 healthy children without congenital anomalies served as controls. Cut-off points were established using likeli-hood ratio values. Results The mean concentration of malonylcarnitine in the cleft group was lower than that of the control group, 0.048 μmol.L^1 vs. 0.058 μmol.L^-1, respectively （P=-0.009）. In patients with orofacial cleft, low malonylcarnitine levels （〈0.047 μmol.L-1） were 1.7 times more predominant than in healthy individuals （P=-0.03）. The mean concentration of acetylcarnitine was also lower in affected newborns in comparison to controls, 33.8 μol.L^-1 vs. 37.8 μmol·L^-1, respectively （P=-0.026）. After analysis of acetylearnitine and free carnitine concentrations, the likelihood ratio test did not indicate valuable cut-offpoints. Conclusion The study provides initial data indicating a potential association between decreased malonylcarnitine and abnormal palatogenesis.

关键词： cleft palate malonyl-CoA carnitines fatty acids biotin

Disruption of interstitial cells of Cajal networks after massive small bowel resection

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World Journal of Gastroenterology 2013年第22期19卷 3415-3422页

作者： Jie Chen Lei Du Yong-Tao Xiao Wei Cai Department of pediatric Surgery Xin Hua Hospital Shanghai Jiaotong University School of Medicine Department of pediatric Surgery School of Medicine Affiliated Hospital of Nantong University Shanghai Key Laboratory of pediatric Gastroenterology and Nutrition Shanghai Institute of Pediatric Research Shanghai Jiaotong University

AIM: To investigate the disruptions of interstitial cells of Cajal (ICC) in the remaining bowel in rats after massive small bowel resection (mSBR). METHODS: Thirty male Sprague-Dawley rats fitting entry criteria were divided randomly into three experimental groups (n = 10 each): Group A rats underwent bowel transection and re-anastomosis (sham) and tissue samples were harvested at day 7 post-surgery. Group B and C rats underwent 80% small bowel resection with tissue harvested from Group B rats at day 7 post-surgery, and from Group C rats at day 14 postsurgery. The distribution of ICC at the site of the resid-ual small bowel was evaluated by immunohistochemical analysis of small intestine samples. The ultrastructural changes of ICC in the remnant ileum of model rats 7 and 14 d after mSBR were analyzed by transmission electron microscopy. Intracellular recordings of slow wave oscillations were used to evaluate electrical pacemaking. The protein expression of c-kit, ICC phenotypic markers, and membrane-bound stem cell factor (mSCF) in intestinal smooth muscle of each group were detected by Western blotting. RESULTS: After mSBR, immunohistochemical analysis indicated that the number of c-kit-positive cells was dramatically decreased in Group B rats compared with sham tissues. Significant ultrastructural changes in ICC with associated smooth muscle hypertrophy were also observed. Disordered spontaneous rhythmic contractions with reduced amplitude (8.5 ± 1.4 mV vs 24.8 ± 1.3 mV, P = 0.037) and increased slow wave frequency (39.5 ± 2.1 cycles/min vs 33.0 ± 1.3 cycles/min, P = 0.044) were found in the residual intestinal smooth muscle 7 d post mSBR. The contractile function and electrical activity of intestinal circular smooth muscle returned to normal levels at 14 d post mSBR (amplitude, 14.9 ± 1.6 mV vs 24.8 ± 1.3 mV; frequency, 30.7 ± 1.7 cycles/min vs 33.0 ± 1.3 cycles/min). The expression of Mscf and c-kit protein was decreased at 7 d (P = 0.026), but gradually returne

关键词： Interstitial cells of Cajal c-kit Slow wave Massive small bowel resection Intestinal dysfunction

Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

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Neural Regeneration Research 2025年第9期20卷 2633-2644页

作者： Zhimin Long Chuanhua Ge Yueyang Zhao Yuanjie Liu Qinghua Zeng Qing Tang Zhifang Dong Guiqiong He Institute of Neuroscience School of Basic Medical SciencesChongqing Medical UniversityChongqingChina Department of Anatomy Chongqing Medical UniversityChongqingChina Department of Physiology Chongqing Medical UniversityChongqingChina pediatric Research Institute Children’s Hospital of Chongqing Medical UniversityChongqingChina Ministry of Education Key Laboratory of Child Development and Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina National Clinical Research Center for Child Health and Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders Children’s Hospital of Chongqing Medical UniversityChongqingChina

Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque ***,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's *** acetylation/deacetylation plays a central role in lysosomal ***,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's *** rthermore,we found that treatment with valproic acid markedly enhanced *** clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's *** findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

关键词： Alzheimer's disease amyloid-β APP/PS1 mice autophagy cognitive impairment histone deacetylase 6 lysosomal acidification microtubule acetylation valproic acid V-ATPase

IL-17,a new kid on the block of tertiary lymphoid organs

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Cellular & Molecular Immunology 2012年第1期9卷 3-4页

作者： Theresa T Lu Hajeong Kim Xiaojing Ma Autoimmunity and Inflammation program and pediatric Rheumatology Hospital for Special SurgeryNew YorkNYUSA Department of Microbiology and Immunology Weill Cornell Medical CollegeNew YorkNYUSA

T ertiary lymphoid organs(TLOs)are structures that resemble lymph nodes that can be found in chronically inflamed tissues in a number of inflammatory *** can host ongoing immune responses that can potentially contribute to disease *** development of TLOs has been thought in large part to recapitulate the development of secondary lymphoid organs,but the regulation of TLO development has not been well *** a recent article in Nature Immunology,Troy Randall and colleagues1 identify IL-17,a cytokine that contributes to the pathogenesis of a number of inflammatory diseases,as a novel critical player in TLO formation in inflamed *** can be found in the joints of patients with rheumatoid arthritis,in the inflamed salivary glands of patients with Sjogren’s syndrome,in the meninges of patients with multiple sclerosis,and in the lungs of patients with pulmonary inflammation or *** the lungs,induced bronchus-associated lymphoid tissues(iBALTs)are TLOs that are located along the small airways.

关键词： organs lymphoid pathogenesis

High frequency of CD34+CD38-/low immature leukemia cells is correlated with unfavorable prognosis in acute myeloid leukemia

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World Journal of Stem Cells 2017年第12期9卷 227-234页

作者： Adriana Plesa Charles Dumontet Eve Mattei Ines Tagoug Sandrine Hayette Pierre Sujobert Isabelle Tigaud Marie Pierre Pages Youcef Chelghoum Fiorenza Baracco Helene Labussierre Sophie Ducastelle Etienne Paubelle Franck Emmanuel Nicolini Mohamed Elhamri Lydia Campos Claudiu Plesa Stéphane Morisset Gilles Salles Yves Bertrand Mauricette Michallet Xavier Thomas Laboratory of Hematology Lyon-Sud HospitalHospices Civils de Lyon CRCL INSERM 1052/CNRS 5286 Department of Hematology Hospices Civils de Lyon Laboratory of Hematology Nord Hospital Statistical and Clinical Research Lyon-Sud HospitalHospices Civils de Lyon Department of pediatric Hematology and bmt IHOP Lyon

AIM To evaluate the importance of the CD34+CD38-cell population when compared to the CD34+CD38+/low and CD34+CD38+/high leukemic cell sub-populations and to determine its correlations with leukemia characteristics and known prognostic factors, as well as with response to therapy and *** Two hundred bone marrow samples were obtained at diagnosis from 200 consecutive patients with newly diagnosed acute myeloid leukemia(AML) were studied between September 2008 and December 2010 at our Institution(Hematology Department, Lyon, France). The CD34/CD38 cell profile was analyzed by multiparameter flowcytometry approach using 8 C panels and FACS CANTO and Diva software(BD Bioscience).RESULTS We analyzed CD34 and CD38 expression in bone marrow samples of 200 AML patients at diagnosis, and investigated the prognostic value of the most immature CD34+CD38-population. Using a cut-off value of 1% of CD34+CD38-from total "bulk leukemic cells" we found that a high(> 1%) level of CD34+CD38-blasts at diagnosis was correlated with advanced age, adverse cytogenetics as well as with a lower rate of complete response after induction and shorter disease-free survival. In a multivariate analysis considering age, leukocytosis, the % of CD34+ blasts cells and the standardized cytogenetic and molecular risk subgroups, a percentage of CD34+CD38-leukemic cells > 1% was an independent predictor of DFS [HR = 2.8(1.02-7.73), P = 0.04] and OS [HR = 2.65(1.09-6.43), P = 0.03].CONCLUSION Taken together, these results show that a CD34/CD38 "backbone" for leukemic cell analysis by multicolour flowcytometry at diagnosis provides useful prognostic information.

关键词： CD34+CD38-/low Immunophenotyping Leukemic stem cells Acute myeloid leukemia Prognosis

Toward developing a simulated workplace laboratory for adults with high functioning autism spectrum disorders

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Open Journal of Psychiatry 2013年第3期3卷 316-322页

作者： Ronna Fried Gagan Joshi Amelia Kotte Elana Kagan Joseph Biederman pediatric Psychopharmacology program Massachusetts General Hospital Boston USA

Objective: Adults with high functioning autism spectrum disorders (HF-ASD) often experience difficulty in sustaining employment, yet little is known about workplace deficits in this population. This study aimed to assess the workplace performance of individuals with HF-ASDs in a previously validated laboratory workplace simulation environment. Method: Seven subjects of both sexes, ages 18 - 21 with a clinical diagnosis of ASD were brought in for a 10- hour workplace simulation, with a series of structured and unstructured tasks designed to elicit DSM-IV Attention Deficit and Hyperactivity Disorder (ADHD) symptoms and to provide objective measures of workplace performance. Results: HF-ASD participants performed significantly worse than Controls on several tasks throughout the day, particularly in the afternoon. Although HF-ASD subjects did not report elevated symptoms of ADHD, they completed significantly less of the unstructured tasks than Controls. Conclusion: These findings suggest that unstructured work activities and a lack of self-awareness are two primary areas of workplace deficits for individuals with HF-ASD.

关键词： Workplace Employment Autism Spectrum Disorder Self-Report

Low interleukin-10 level indicates a good prognosis in Salmonella enterica serovar typhimurium-induced pediatric hemophagocytic lymphohistiocytosis:A case report

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World Journal of Clinical Cases 2024年第9期12卷 1660-1668页

作者： Yuan-Yuan Chen Xiang-Zhi Xu Xiao-Jun Xu Division/Center of pediatric Hematology Oncology Children’s HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina pediatric Intensive Care unit Children’s Hospital of Zhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina

BACKGROUND Secondary hemophagocytic lymphohistiocytosis(sHLH)triggered by Salmonella enterica serovar Typhimurium is rare in pediatric *** is no consensus on how to treat ***-triggered *** SUMMARY A 9-year-old boy with intermittent fever for 3 d presented to our hospital with positive results for ***,human rhinovirus,and Mycoplasma pneumoniae *** the time of admission to our institution,the patient’s T helper 1/T helper 2 cytokine levels were 326 pg/mL for interleukin 6(IL-6),9.1 pg/mL for IL-10,and 246.7 pg/mL for interferon-gamma(IFN-γ),for which the ratio of IL-10 to IFN-γwas *** this study,the patient received meropenem,linezolid,and cefoperazone/sulbactam in combination with high-dose methylprednisolone therapy(10 mg/kg/d for 3 d)and antishock supportive treatment *** careful evaluation,this patient did not receive HLH chemotherapy and recovered *** *** infection-triggered sHLH patient had a ratio of IL-10 to IFN-γ≤1.33,an IL-10 concentration≤10.0 pg/mL,and/or an IFN-γconcentration≤225 pg/mL at *** antimicrobial and supportive treatment was sufficient,and the HLH-94/2004 protocol was not necessary under these conditions.

关键词： Hemophagocytic lymphohistiocytosis Cytokine pattern Interferon gamma Interleukin-10 Salmonella enterica serovar Typhimurium Case report